2-oxindole compounds which are useful as tyrosine kinase inhibitors

ABSTRACT

Aryl- and heteroarylethenylene derivatives of formula ##STR1## wherein Y is a mono- or bicyclic ring system chosen from (A), (B), (C), (D), (E), (F) and (G) ##STR2## R is a group of formula  R 1  is hydrogen, C 1  -C 6  alkyl or C 2  -C 6  alkanoyl; R 2  is hydrogen, halogen, cyano or C 1  -C 6  alkyl; 
     n is zero or an integer of 1 to 3: n is zero or an integer of 1 to 3 when Y is a ring system (A); it is zero, 1 or 2 when Y is a ring system (B), (E), (F) or (G); or it is zero or 1 when Y is a ring system (C) or (D); and the pharmaceutically acceptable salts thereof; and wherein each of the substituents R, OR 1  and R 2  may be independently on either of the aryl or heteroaryl moieties of the bicyclic ring system (A), (E), (F) and (G), whereas only the benzene moiety may be substituted in the bicyclic ring system (B), are useful as tyrosine kinase activity inhibitors.

This application is a continuation of application Ser. No. 07/768,259,filed on Oct. 28, 1991, now abandoned.

The present invention relates to new aryl- and heteroarylethenylenederivatives, to a process for their preparation, to pharmaceuticalcompositions containing them and to their use as therapeutic agents.

The present invention provides compounds having the following generalformula (I) ##STR3## wherein Y is a mono- or bicyclic ring system chosenfrom (A), (B), (C), (D), (E), (F) and (G) ##STR4## R is a group offormula (a), (b), (c), (d), (e), (f), (g), (h), (i) or (j) ##STR5## inwhich R₃ is --OH or --NH₂ and Ph means phenyl; R₁ is hydrogen, C₁ -C₆alkyl or C₂ -C₆ alkanoyl; R₂ is hydrogen, halogen, cyano or C₁ -C₆alkyl; n is zero or an integer of 1 to 3: n is zero or an integer of 1to 3 when Y is a ring system (A); it is zero, 1 or 2 when Y is a ringsystem (B), (E), (F) or (G); or it is zero or 1 when Y is a ring system(C) or (D); and the pharmaceutically acceptable salts thereof; andwherein each of the substituents R, OR₁ and R₂ may be independently oneither of the aryl or heteroaryl moieties of the bicyclic ring system(A), (E), (F) and (G), whereas only the benzene moiety may besubstituted in the bicyclic ring system (B).

The invention includes within its scope all the possible isomers,stereoisomers, in particular Z and E isomers and their mixtures, and themetabolites and the metabolic precursors or bio-precursors (otherwiseknown as pro-drugs) of the compounds of formula (I).

The substituent R is preferably linked to position 1 or 2 in ring system(A) and (B), to position 4 in ring system (C) and (D), to position 5 or8 in ring system (E) and (F) and to position 3 or 7 in ring system (G).The substituent R₂ may be independently on either of the rings in thebicyclic ring systems (A), (B), (E), (F) and (G).

When Y is a bicyclic ring system as defined under (A), (E) or (F) the--OR₁ groups are preferably on the same benzene moiety as the R group.In any of ring systems (A) to (G), the substituent R₂ is preferablylocated on the same 6-membered ring as the substituent --OR₁ in theortho-, meta-or para- position with respect to --OR₁. Preferably R₂ islocated in a position ortho- or para- to --OR₁.

A substituent --OR₁ is preferably linked to position 1, 2, 3, 4, 5 or 8,in particular to position 1, 2, 3 or 4, in ring systems (A) and (B). Asubstituent --OR₁ is preferably linked to position 2, 3, 4 or 5, inparticular to position 3, 4 or 5, in ring systems (C) and (D). Asubstituent --OR₁ is preferably linked to position 3, 4, 5, 6, 7 or 8,in particular to position 5, 6, 7 or 8, in ring system (E) and (F). Asubstituent --OR₁ is preferably linked to position 3, 4, 5, 6 or 7, inparticular to position 4, 5, 6 or 7 in ring system (G). Of course onlyone of the substituents R, --OR₁ and R₂ can be linked to the sameposition in ring systems (A) to (G).

When n is 2 or 3, the --OR₁ groups may be the same or different.

The alkyl groups, and the alkyl moiety in the alkanoyl groups, may be abranched or straight alkyl chain. A C₁ -C₆ alkyl group is preferably aC₁ -C₄ alkyl group, e.g. methyl, ethyl, propyl, isopropyl, butyl,sec-butyl or tert-butyl, in particular methyl or ethyl. A C₂ -C₆alkanoyl group is preferably a C₂ -C₄ alkanoyl group, in particularacetyl, propionyl or butyryl.

A halogen is, preferably, chlorine, bromine or fluorine, in particularbromine.

Pharmaceutically acceptable salts of the compounds of the inventioninclude acid addition salts, with inorganic, e.g. nitric, hydrochloric,hydrobromic, sulphuric, perchloric and phosphoric acids, or organic,e.g. acetic, propionic, glycolic, lactic, oxalic, malonic, malic,maleic, tartaric, citric, benzoic, cinnamic, mandelic and salicylicacids, and salts with inorganic, e.g. alkali metal, especially sodium orpotassium, bases or alkaline-earth metal, especially calcium ormagnesium bases, or with organic bases, e.g. alkylamines, preferablytriethyl-amine.

As stated above the present invention also includes within its scopepharmaceutically acceptable bio-precursors (otherwise known aspro-drugs) of the compounds of formula (I), i.e. compounds which have adifferent formula to formula (I) above but which nevertheless uponadministration to a human being are converted directly or indirectly invivo into a compound of formula (I). Preferred compounds of theinvention are the compounds of formula (I), wherein

Y is a monocyclic or bicyclic ring system chosen from (A) to (G), asdefined above;

R is a group of formula (a), (b), (c), (d), (e), (i) or (j) as definedabove;

R₁ is hydrogen, C₁ -C₄ alkyl or C₂ -C₄ alkanoyl;

R₂ is hydrogen;

n is a defined above; and the pharmaceutically acceptable salts thereof.

More preferred compounds of the invention are the compounds of formula(I), wherein

Y is a bicyclic ring system of formula (A), (B) or (E), as definedabove;

R is a group of formula (a), (d), (e), (i) or (j), as defined above; R₁and R₂ are hydrogen;

n is zero or 1; and the pharmaceutically acceptable salts thereof.

Examples of specific compounds of the invention are the followingcompounds which, when appropriate, may be either Z- or E- diastereomersor Z, E- mixtures of said diastereomers:

2-cyano-3-(2-hydroxynaphth-1-yl)acrylamide;

2-cyano-3-(3-hydroxynaphth-1-yl)acrylamide;

2-cyano-3-(4-hydroxynaphth-1-yl)acrylamide;

2-cyano-3-(1-hydroxynaphth-2-yl)acrylamide;

2-cyano-3-(3-hydroxynaphth-2-yl)acrylamide;

2-cyano-3-(4-hydroxynaphth-2-yl)acrylamide;

2-cyano-3-(2-hydroxynaphth-1-yl)acrylic acid;

2-cyano-3-(3-hydroxynaphth-1-yl)acrylic acid;

2-cyano-3-(4-hydroxynaphth-1-yl)acrylic acid;

2-cyano-3-(1-hydroxynaphth-2-yl) acrylic acid;

2-cyano-3-(3-hydroxynaphth-2-yl) acrylic acid;

2-cyano-3-(4-hydroxynaphth-2-yl) acrylic acid;

2-cyano-3-(2-hydroxynaphth-1-yl)thioacrylamide;

2-cyano-3-(3-hydroxynaphth-1-yl)thioacrylamide;

2-cyano-3-(4-hydroxynaphth-1-yl)thioacrylamide;

2-cyano-3-(1-hydroxynaphth-2-yl)thioacrylamide;

2-cyano-3-(3-hydroxynaphth-2-yl)thioacrylamide;

2-cyano-3-(4-hydroxynaphth-2-yl)thioacrylamide;

2-(4-hydroxyphenyl)-3-(naphth-1-yl)acrylamide;

2-(4-hydroxyphenyl)-3-(naphth-2-yl)acrylamide;

2-(4-hydroxyphenyl)-3-(naphth-1-yl)acrylic acid;

2-(4-hydroxyphenyl)-3-(naphth-2-yl)acrylic acid;

2-cyano-3-(2-hydroxy-5,6,7,8-tetrahydronaphth-1-yl)acrylamide;

2-cyano-3-(3-hydroxy-5,6,7,8-tetrahydronaphth-1-yl)acrylamide;

2-cyano-3-(4-hydroxy-5,6,7,8-tetrahydronaphth-1-yl)acrylamide;

2-cyano-3-(1-hydroxy-5,6,7,8-tetrahydronaphth-2-yl)acrylamide;

2-cyano-3-(3-hydroxy-5,6,7,8-tetrahydronaphth-2-yl)acrylamide;

2-cyano-3-(4-hydroxy-5,6,7,8-tetrahydronaphth-2-yl)acrylamide;

2-cyano-3-(2-hydroxy-5,6,7,8-tetrahydronaphth-1-yl)acrylic acid;

2-cyano-3-(3-hydroxy-5,6,7,8-tetrahydronaphth-1-yl)acrylic acid;

2-cyano-3-(4-hydroxy-5,6,7,8-tetrahydronaphth-1-yl)acrylic acid;

2-cyano-3-(1-hydroxy-5,6,7,8-tetrahydronaphth-2-yl)acrylic acid;

2-cyano-3(3-hydroxy-5,6,7,8-tetrahydronaphth-2-yl)acrylic acid;

2cyano-3-(4-hydroxy-5,6,7,8-tetrahydronaphth-2-yl)acrylic acid

2-cyano-3-(2-hydroxy-5,6,7,8-tetrahydronaphth-1-yl)thioacrylamide;

2-cyano-3-(3-hydroxy-5,6,7,8-tetrahydronaphth-1-yl)thioacrylamide;

2-cyano-3-(4-hydroxy-5,6,7,8-tetrahydronaphth-1-yl)thioacrylamide;

2-cyano-3-(1-hydroxy-5,6,7,8-tetrahydronaphth-2-yl)thioacrylamide;

2-cyano-3-(3-hydroxy-5,6,7,8-tetrahydronaphth-2-yl)thioacrylamide;

2-cyano-3-(4-hydroxy-5,6,7,8-tetrahydronaphth-2-yl)thioacrylamide;

2-(4-hydroxyphenyl)-3-(5,6,7,8-tetrahydronaphth-1-yl)acrylamide;

2-(4-hydroxyphenyl)-3-(5,6,7,8-tetrahydronaphth-2-yl)acrylamide;

2-(4-hydroxphenyl)-3-(5,6,7,8-tetrahydronaphth-1-yl)acrylic acid;

2-(4-hydroxyphenyl)-3-(5,6,7,8-tetrahydronaphth-2-yl)acrylic acid;

2-cyano-3-(3-hydroxyquinolin-2-yl)acrylamide;

2-cyano-3-(4-hydroxyquinolin-2-yl)acrylamide;

2-cyano-3-(2-hydroxyquinolin-3-yl)acrylamide;

2-cyano-3-(4-hydroxyquinolin-3-yl)acrylamide;

2-cyano-3-(2-hydroxyquinolin-4-yl)acrylamide;

2-cyano-3-(3-hydroxyquinolin-4-yl)acrylamide;

2-cyano-3-(3-hydroxyquinolin-2-yl)acrylic acid;

2-cyano-3-(4-hydroxyquinolin-2-yl)acrylic acid;

2-cyano-3-(2-hydroxyquinolin-3-yl)acrylic acid;

2-cyano-3-(4-hydroxyquinolin-3-yl)acrylic acid;

2-cyano-3-(2-hydroxyquinolin-4-yl)acrylic acid;

2-cyano-3-(3-hydroxyquinolin-4-yl)acrylic acid;

2-cyano-3-(3-hydroxyquinolin-2-yl)thioacrylamide;

2-cyano-3-(4-hydroxyquinolin-2-yl)thioacrylamide;

2-cyano-3-(2-hydroxyquinolin-3-yl)thioacrylamide;

2-cyano-3-(4-hydroxyquinolin-3-yl)thioacrylamide;

2-cyano-3-(2-hydroxyquinolin-4-yl)thioacrylamide;

2-cyano-3-(3-hydroxyquinolin-4-yl)thioacrylamide;

2-(4-hydroxyphenyl)-3-(quinolin-2-yl)acrylamide;

2-(4-hydroxyphenyl)-3-(quinolin-3-yl)acrylamide;

2-(4-hydroxyphenyl)-3-(quinolin-4-yl)acrylamide;

2-(4-hydroxyphenyl)-3-(quinolin-2-yl)acrylic acid;

2-(4-hydroxyphenyl)-3-(quinolin-3-yl)acrylic acid;

2-(4-hydroxyphenyl)-3-(quinolin-4-yl)acrylic acid;

3-[(3-hydroxy-1-naphthyl)methylene]-2-oxindole;

3-[(4-hydroxy-1-naphthyl)methylene]-2-oxindole;

3-[(1-hydroxy-2-naphthyl)methylene]-2-oxindole;

3-[(4-hydroxy-2-naphthyl)methylene]-2-oxindole;

3-[(3-hydroxy-5,6,7,8-tetrahydronaphth-1-yl)methylene]-2-oxindole;

3-[(4-hydroxy-5,6,7,8-tetrahydronaphth-1-yl)methylene]-2-oxindole;

3-[(1-hydroxy-5,6,7,8-tetrahydronaphth-2-yl)methylene]-2-oxindole;

3-[(4-hydroxy-5,6,7,8-tetrahydronaphth-2-yl)methylene]-2-oxindole;

3-[(7-hydroxyquinolin-5-yl)methylene]-2-oxindole;

3-[(8-hydroxyquinolin-5-yl)methylene]-2-oxindole;

3-[(7-hydroxyquinolin-6-yl)methylene]-2-oxindole;

3-[(8-hydroxyquinolin-6-yl)methylene]-2-oxindole,

and, if the case, the pharmaceutically acceptable salts thereof.

The compounds of the invention, and the pharmaceutically acceptablesalts thereof, can be obtained by a process comprising the condensationof an aldehyde of formula (II) ##STR6## wherein Y, R₁, R₂ and n are asdefined above with a compound of formula (a'), (b'), (c'), (d'), (e'),(f'), (g'), (h'), (i') or (j'), respectively, ##STR7## wherein R₃ and Phare as defined above; and if desired, converting a compound of formula(I) into another compound of formula (I), and/or, if desired, convertinga compound of formula (I) into a pharmaceutically acceptable saltthereof, and/or, if desired, converting a salt into a free compound,and/or, if desired, separating a mixture of isomers of a compound offormula (I) into the single isomers. The reaction of a compound offormula (II) with a compound of formula (a'), (b'), (c'), (d'), (e'),(f'), (g'), (h'), (i') or (j'), is an analogy process which can becarried out according to known methods, as herebelow described;preferably in the presence of a basic catalyst, e.g. pyridine,piperidine, dimethylamine, or a suitable alkali/metal hydroxide oralkoxide.

For example the reaction of a compound of formula (II) with a compoundof formula (a'), (b'), (c'), (d'), (e'), (f'), (g') or (h'),respectively, may be carried out under the conditions of the Knoevenagelreactions as described e.g. by G. Jones in Organic Reactions 15, 204(1967). Suitable catalyst are organic bases such as pyridine, piperidineor diethylamine. The condensation may be performed in an inert organicsolvent e.g. pyridine, ethanol, methanol, benzene or dioxane attemperature ranging from about 0° C. to about 100° C. Preferably thereaction is carried out in warm ethanol solution in the presence ofpiperidine catalyst.

The reaction of a compound of formula (II) with a compound of formula(d') may be carried out according to the Knoevenagel method as describedabove but using special conditions. Especially higher reactiontemperatures are used in consideration of the fact that during thecondensation also a decarboxylation occurs. For instance thecondensation may be performed in an organic base such as pyridine (whichat same time is solvent and catalyst) at temperatures ranging from about50° to about 140° C.

The reaction of a compound of formula (II) with a compound of formula(i') may be carried out as described by R. E. Buckles et al. in J. Am.Chem. Soc. 73, 4972 (1951). According to this method equimolar amountsof the aromatic aldehyde and the phenylacetic derivative are reacted in3-5 molequivalents of acetic anhydride in the presence of about 1molequivalent triethylamine at temperatures ranging from about 100° toabout 140° C.

The condensation of a compound of formula (II) with a compound offormula (j') may be carried out in alcoholic solution using a metalalkoxide, e.g. sodium ethoxide, potassium t-butoxide, or a metalhydroxide, e.g. sodium hydroxide, as catalyst; at temperatures rangingfrom about 0° C. to about 100° C. Preferably equimolar amounts ofreactants are condensed in ethanol solution at room temperature in thepresence of sodium ethoxide using about 1 molequivalent for each acidichydrogen of the latter.

A compound of formula (I) can be converted into another compound offormula (I) according to known methods. For example thede-etherification of a compound of formula (I), wherein one or more R₁substituents are C₁ -C₆ alkyl, so as to obtain a compound of formula (I)wherein one or more R₁ substituents are hydrogen may be performed bywell known methods in organic chemistry. In the case of a phenolicmethyl ether the cleavage can be carried out for example with borontribromide as described by J. F. N. McOmie in Tetrahedron 24, 2289(1968). It is advisable to use about 1 mole of boron tribromide for eachether group, together with an extra mol of reagent for each groupcontaining a potentially basic nitrogen or oxygen. The reaction may beperformed in an inert organic solvent such as methylene chloride,pentane or benzene under an inert, e.g. nitrogen, atmosphere attemperatures ranging from about -78° C. to about room temperature. Theacylation of a compound of formula (I) wherein one or more R₁substituent is hydrogen, so as to obtain a corresponding compound offormula (I) wherein one or more R₁ substituent is a C₂ -C₆ alkanoylgroup, may be obtained by reaction with a reactive derivative of asuitable carboxylic acid, such as an anhydride or halide, in thepresence of a basic agent, at temperatures ranging from about 0° C. toabout 50° C. Preferably the acylation is carried out by reaction withthe respective anhydride in the presence of an organic base, such aspyridine. Analogously the conversion of a compound of formula (I),wherein R is a group of formula ##STR8## into another compound offormula (I) wherein R is a group of formula ##STR9## respectively, maybe carried out according to known methods. For example a reactivederivative of the carboxylic acid, e.g. a suitable halide, preferablythe chloride, can be reacted with aqueous ammonium hydroxide solution ata temperature ranging from about 5° C. to about 40° C.

The optional salification of a compound of formula (I) as well as theconversion of a salt into the free compound and the separation of amixture of isomers into the single isomers may be carried out byconventional methods.

For example the separation of a mixture of geometric isomers, e.g. cis-and trans-isomers, may be carried out by fractional crystallization froma suitable solvent or by chromatography, either column chromatography orhigh pressure liquid chromatography.

The compounds of formula (II) may be obtained according to known methodsfrom compounds of formula (III). ##STR10## wherein Y, R₁, R₂ and n areas defined above.

For example the phenolic compound of formula (III) may be treated withchloroform and alkali hydroxides in an aqueous or aqueous alcoholicsolution according to the well known method of Reimer-Tiemann. If thestarting material is an aromatic methylether the method described by N.S. Narasimhan et al. in Tetrahedron 31, 1005 (1975) can be applied.Accordingly the methylether of formula (III) is lithiated with butyllithium in refluxing ether. Treatment of the organometallic compoundwith N-methylformanilide furnishes the formyl derivative. The compoundsof formula (III) are known or may be obtained by known methods fromknown compounds.

PHARMACOLOGY

The compounds of the present invention possess specific tyrosine kinaseinhibiting activity. Hence they can be useful in the treatment of cancerand other pathological proliferative conditions.

Recent studies on the molecular basis of neoplastic transformation haveidentified a family of genes, designed oncogenes, whose aberrantexpression causes tumorigenesis.

For example, the RNA tumor viruses possess such an oncogene sequencewhose expression determines neoplastic conversion of infected cells.Several of their oncogene-encoded proteins, such as pp60^(v-src),p70^(gag-yes), p130^(gag-fps) and p70^(gag-fgr) display protein tyrosinekinase activity, that is they catalyse the transfer of the γ-phosphatefrom adenosine triphosphate (ATP) to tyrosine residues in proteinsubstrate. In normal cells, several growth factor receptors, for examplethe receptors for PDGF, EGF, α-TGF and insulin, display tyrosine kinaseactivity. Binding of the growth factor (GF) activates the receptortyrosine kinase to undergo autophosphorylation and to phosphorylateclosely adjacent molecules on tyrosine.

Therefore, it is thought that the phosphorylation of these tyrosinekinase receptors plays an important role in signal transduction and thatthe principal function of tyrosine kinase activity in normal cells is toregulate cell growth. Perturbation of this activity by oncogenictyrosine kinase that are either overproduced and/or display alteredsubstrate specificity may cause loss of growth control and/or neoplastictransformation. Accordingly, a specific inhibitor of tyrosine kinasescan be useful in investigating the mechanism of carcinogenesis, cellproliferation and differentiation and it can be effective in preventionand chemotherapy of cancer and in other pathological proliferativeconditions. The tyrosine specific protein kinase activity of thesecompounds is shown, e.g., by the fact that they are active in the invitro test described by B. Ferguson et al., in J. Biol. Chem. 1985, 260,3652.

The enzyme used is the Abelson tyrosine kinase p 60^(v-abl). Itsproduction and isolation is performed according to a modification of themethod of B. Ferguson et al. (ibidem). As substrate α-casein or(Val⁵)-angiotensin is used.

The inhibitor is preincubated with the enzyme for 5 min at 25° C. Thereaction conditions are:

100 mM MOPS buffer, 10 mM MgCl₂, 2 μM (γ-³² P) ATP (6Ci/mmol), 1 mg/mlα-casein [an alternative substrate is (Val⁵) angiotensin II] and 7.5μg/ml of enzyme in a total volume of 30 μl and pH 7.0.

The reaction is incubated for 10 min at 25° C. Trichloroacetic acidprecipitation of protein is followed by rapid filtration andquantification of phosphorylated substrate by a liquid scintillationcounter. Alternatively the reaction mixture is subjected to sodiumdodecyl sulfate -polyacrylamide electrophoresis and the phosphorylatedsubstrate measured by autoradiography or P³² -counting of the excisedspot.

In view of their high activity and low toxicity, the compounds of theinvention can be used safely in medicine.

For example, the approximate acute toxicity (LD₅₀) of the compounds ofthe invention in the mouse, determined by single administration ofincreasing doses and measured on the seventh day after the treatment wasfound to be negligible.

The compounds of the invention can be administered in a variety ofdosage forms, e.g. orally, in the form of tablets, capsules, sugar offilm coated tablets, liquid solutions or suspensions; rectally, in theform of suppositories; parenterally, e.g. intramuscularly, or byintravenous injection of infusion; or topically.

The dosage depends on the age, weight, conditions of the patient andadministration route; for example the dosage adopted for oraladministration to adult humans may range from about 10 to about 150-200mg pro dose, from 1 to 5 times daily.

Of course, these dosage regimens may be adjusted to provide the optimaltherapeutic response.

The invention includes pharmaceutical compositions comprising a compoundof the invention in association with a pharmaceutically acceptableexcipient (which can be a carrier or diluent).

The pharmaceutical compositions containing the compounds of theinvention are usually prepared following conventional methods and areadministered in a pharmaceutically suitable form.

For example, the solid oral forms may contain, together with the activecompound, diluents, e.g., lactose, dextrose, saccharose, cellulose, cornstarch or potato starch; lubricants, e.g. silica, talc, stearic acid,magnesium or calcium stearate, and/or polyethylene glycols; bindingagents, e.g. starches, arabic gums, gelatin, methylcellulose,carboxymethylcellulose or polyvinyl pyrrolidone; disaggregating agents,e.g. a starch, alginic acid, alginates or sodium starch glycolate,effervescing mixtures; dyestuffs; sweeteners; wetting agents, such aslecithin, polysorbates, laurylsulphates; and, in general, non-toxic andpharmacologically inactive substances used in pharmaceuticalformulations. Said pharmaceutical preparations may be manufactured inknown manner, for example, by means of mixing, granulating, tablettingsugar-coating or film-coating processes.

The liquid dispersion for oral administration may be e.g. syrups,emulsions and suspensions.

The syrup may contain as carrier, for example, saccharose or saccharosewith glycerine and/or mannitol and/or sorbitol. The suspensions and theemulsions may contain as carrier, for example, a natural gum, agar,sodium alginate, pectin, methylcellulose, carboxymethylcellulose orpolyvinyl alcohol. The suspensions or solutions for intramuscularinjections may contain, together with the active compound, apharmaceutically acceptable carrier, e.g. sterile water, olive oil,ethyl oleate, glycols, e.g. propylene glycol, and, if desired, asuitable amount of lidocaine hydrochloride. The solutions forintravenous injections or infusion may contain as carrier, for example,sterile water or, preferably, they may be in the form of sterile,aqueous, isotonic saline solutions.

The suppositories may contain together with the active compound apharmaceutically acceptable carrier, e.g. cocoa-butter, polyethyleneglycol, a polyoxyethylene sorbitan fatty acid ester surfactant orlecithin.

Compositions for topical application e.g., creams, lotions or pastes,can be prepared by admixing the active ingredient with a conventionaloleaginous or emulsifying excipient.

The following examples illustrate but do not limit the invention.

EXAMPLE 1

2-cyano-3-(8-hydroxyquinolin-5-yl) acrylamide I,Y=E, R=a, R₁ =R₂ =H,n=1, R₃ =NH₂.

A solution of 5-formyl-8-hydroxyquinoline(173 mg, 1 mmol),cyanoacetamide (92 mg; 1.1 mmol) and piperidine (60 mg, 0.7 mmol) inabsolute ethanol (20 ml) is heated for 4 h at 50° C. The reactionmixture is chilled to 0°-5° C., the precipitate filtered, the residuewashed with ice-cooled ethanol and then dried under vacuum.

Pure title compound is so obtained in 70% yield (167 mg). Compounds ofhigher purity are obtained by crystallization from ethanol,m.p.275°. C₁₃H₉ N₃ O₂ requires: C 65.27 H 3.79 N 17.56 found: C 65.15 H 3.65 N 17.49MS m/z: 239 IR cm⁻¹ (KBr): 3100-3600 (NH,OH), 2200 (CN), 1690 (CONH₂),1610, 1590, 1560, 1510 (C═C)

According to the above described procedure the following compounds canbe prepared:

2-cyano-3-(2-hydroxynaphth-1-yl)acrylamide;

2-cyano-3-(3-hydroxynaphth-1-yl)acrylamide;

2-cyano-3-(4-hydroxynaphth-1-yl)acrylamide;

2-cyano-3-(1-hydroxynaphth-2-yl)acrylamide;

2-cyano-3-(3-hydroxynaphth-2-yl)acrylamide;

2-cyano-3-(4-hydroxynaphth-2-yl)acrylamide;

2-cyano-3-(2-hydroxy-5,6,7,8-tetrahydronaphth-1-yl)acrylamide;

2-cyano-3-(3-hydroxy-5,6,7,8-tetrahydronaphth-1-yl)acrylamide;

2-cyano-3-(4-hydroxy-5,6,7,8-tetrahydronaphth-1-yl)acrylamide;

2-cyano-3-(1-hydroxy-5,6,7,8-tetrahydronaphth-2-yl)acrylamide;

2-cyano-3-(3-hydroxy-5,6,7,8-tetrahydronaphth-2-yl)acrylamide;

2-cyano-3-(4-hydroxy-5,6,7,8-tetrahydronaphth-2-yl)acrylamide;

2-cyano-3-(3-hydroxyquinolin-2-yl)acrylamide;

2-cyano-3-(4-hydroxyquinolin-2-yl)acrylamide;

2-cyano-3-(2-hydroxyquinolin-3-yl)acrylamide;

2-cyano-3-(4-hydroxyquinolin-3-yl)acrylamide;

2-cyano-3-(2-hydroxyquinolin-4-yl)acrylamide;

2-cyano-3-(3-hydroxyquinolin-4-yl)acrylamide;

3-[(1-naphthyl)methylene]-2-oxindole;

3-[(2-hydroxy-1-naphthyl)methylene]-2-oxindole;

3-[3-hydroxy-1-naphthyl)methylene]-2-oxindole;

3-[(4-hydroxy-1-naphthyl)methylene]-2-oxindole;

3-[(2-naphthyl)methylene]-2-oxindole;

3-[(1-hydroxy-2-naphthyl)methylene]-2-oxindole;

3-[(3-hydroxy-2-naphthyl)methylene]-2-oxindole;

3-[(4-hydroxy-2-naphthyl)methylene]-2-oxindole;

3-[(5,6,7,8-tetrahydronaphth-1-yl)methylene]-2-oxindole;

3-[(2-hydroxy-5,6,7,8-tetrahydronaphth-1-yl)methylene]-2-oxindole;

3-[(3-hydroxy-5,6,7,8-tetrahydronaphth-1-yl)methylene]-2-oxindole;

3-[(4-hydroxy-5,6,7,8-tetrahydronaphth-1-yl)methylene]-2-oxindole;

3-[(5,6,7,8-tetrahydronaphth-2-yl)methylene]-2-oxindole;

3-[(1-hydroxy-5,6,7,8-tetrahydronaphth-2-yl)methylene]-2-oxindole;

3-[(3-hydroxy-5,6,7,8-tetrahydronaphth-2-yl)methylene]-2-oxindole;

3-[(4-hydroxy-5,6,7,8-tetrahydronaphth-2-yl)methylene]-2-oxindole;

3-[(quinolin-5-yl)methylene]-2-oxindole;

3-[(6-hydroxyquinolin-5-yl)methylene]-2-oxindole;

3-[(7-hydroxyquinolin-5-yl)methylene]-2-oxindole;

3-[(8-hydroxyquinolin-5-yl)methylene]-2-oxindole;

3-[(quinolin-6-yl)methylene]-2-oxindole;

3-[(5-hydroxyquinolin-6-yl)methylene]-2-oxindole;

3-[(7-hydroxyquinolin-6-yl)methylene]-2-oxindole;

3-[(8-hydroxyquinolin-6-yl)methylene]-2-oxindole;

3-[(1,4-dihydroxy-5,6,7,8-tetrahydronaphth-2-yl)methylene]-2-oxindole,

C₁₉ H₁₇ NO₃ requires: C 74.25 H 5.58 N 4.56 found: C 74.01 H 5.74 N 4.48MS m/z: 307 IR cm⁻¹ (KBr): 3500-3100 (OH,NH), 1670 (CO), 1605 (C═C);3-[(quinolin-2-yl)methylene]-2-oxindole,

C₁₈ H₁₂ N₂ O requires: C 79.39 H 4.44 N 10.29 found: C 79.29 H 4.45 N10.25 MS m/z: 272 IR cm⁻¹ (KBr): 3180 (NH), 1710 (CO), 1620-1595-1505(C═C, C═N); 3-[(4-hydroxyquinolin-2-yl)methylene]-2-oxindole

C₁₈ H₁₂ N₂ O₂ requires: C 74.98 H 4.20 N 9.72 found: C 74.66 H 4.25 N9.38 MS m/z: 288 IR cm⁻¹ (KBr): 3430 (OH,NH), 1675 (CO), 1630 (C═C)1595-1580-1530-1515 (arom); 3-[(quinolin-4-yl)methylene]-2-oxindole,

C₁₈ H₁₂ N₂ O requires: C 79.39 H 4.44 N 10.29;3-[(quinolin-3-yl)methylene]-2-oxindole,

C₁₈ H₁₂ N₂ O requires: C 79.39 H4.44 N 10.29 found: C 79.20 H 4.71 N10.14 MS m/z: 272 IR cm⁻¹ (KBr): 3500-3100 (NH), 1695 (CO),1620-1580-1500 (C═C, C═N);4-[(indol-3-yl)methylene]-1-phenyl-pyrazolidin-3,5-dione,

C₁₈ H₁₃ N₃ O₂ requires: C 71.27 H 4.32 N 13.85 found: C 71.05 H 4.33 N13.64 MS m/z: 303 IR cm⁻¹ (KBr): 3600-3100 (NH), 1705-1650 (CONH),1600-1580-1500 (arom), and 5-[(indol-3-yl)methylene]-hydantoin,

C₁₂ H₉ N₃ O₂ requires: C 63.43 H 3.99 N 18.49 found: C 63.20 H 3.71 N18.31 MS m/z: 227 IR cm⁻¹ (KBr): 3600-3100 (NH), 1740-1700-1650 (CONH),1620-1580-1530 (C═C).

EXAMPLE 2

2-cyano-3-(2-hydroxynaphth-1-yl)thioacrylamide I, Y=A, R=c, R₁ =R₂ =H,n=1

A mixture of 2-hydroxy-1-naphthaldehyde (172 mg, 1 mmol),2-cyanothioacetamide (110 mg, 1.1 mmol), N,N-diethylaminoethanol (23 mg,0.2 mmol) and 15 ml ethanol is stirred for 30 min at reflux undernitrogen. Then the mixture is chilled, the precipitate filtered, washedwith ice-cooled ethanol and dried in a vacuum-oven. Thus an almost puretitle compound is obtained in 85% yield (1080 mg). Recrystallizationfrom ethanol furnishes very pure samples.

C₁₄ H₁₀ N₂ OS requires: C 66.12 H 3.96 N 11.01 S 12.61 found: C 66.05 H3.85 N 10.95 S 12.55 MS m/z: 254 IR cm⁻¹ (KBr): 3300÷2500 (NH, OH), 2020(CN), 1640 (C--N, N--H), 1600-1560-1510 (C═C)

According to the above described procedure the following compounds canbe prepared:

2-cyano-3-(3-hydroxynaphth-1-yl)thioacrylamide;

2-cyano-3-(4-hydroxynaphth-1-yl)thioacrylamide;

2-cyano-3-(1-hydroxynaphth-2-yl)thioacrylamide;

2-cyano-3-(3-hydroxynaphth-2-yl)thioacrylamide;

2-cyano-3-(4-hydroxynaphth-2-yl)thioacrylamide;

2-cyano-3-(2-hydroxy-5,6,7,8-tetrahydronaphth-1-yl)thioacrylamide;

2-cyano-3-(3-hydroxy-5,6,7,8-tetrahydronaphth-1-yl)thioacrylamide;

2-cyano-3-(4-hydroxy-5,6,7,8-tetrahydronaphth-1-yl)thioacrylamide;

2-cyano-3-(1-hydroxy-5,6,7,8-tetrahydronaphth)-2-yl)thioacrylamide;

2-cyano-3-(3-hydroxy-5,6,7,8-tetrahydronaphth-2-yl)thioacrylamide;

2-cyano-3-(4-hydroxy-5,6,7,8-tetrahydronaphth-2-yl)thioacrylamide;

2-cyano-3-(3-hydroxyquinolin-2-yl)thioacrylamide;

2-cyano-3-(4-hydroxyquinolin-2-yl)thioacrylamide;

2-cyano-3-(2-hydroxyquinolin-3-yl)thioacrylamide;

2-cyano-3-(4-hydroxyquinolin-3-yl)thioacrylamide;

2-cyano-3-(2-hydroxyquinolin-4-yl)thioacrylamide;

2-cyano-3-(3-hydroxyquinolin-4-yl)thioacrylamide, and

2-cyano-3-(8-hydroxyquinolin-5-yl)thioacrylamide,

C₁₃ H₉ N₃ OS requires: C 61.16 H 3.55 N 16.46 found: C 60.99 H 3.59 N16.26 MS m/z: 255 IR cm⁻¹ (KBr): 3440 (OH), 3330-3180 (NH), 2220 (CN),1650 (NH), 1610-1570-1510 (C═C, C═N).

EXAMPLE 3

2-cyano-3-(1-hydroxynaphth-2-yl)acrylic acid I, Y=A, R=a, R₁ =R₂ =H, R₃=OH, n=1

To a mixture of 1-hydroxy-2-naphthaldehyde (172 mg, 1 mmol) andcyanoacetic acid (85 mg, 1 mmol) in dry dioxane (2 ml) piperidine (42mg, 0.5 mmol) is added dropwise at 0°-5° C.

The mixture is kept overnight at room temperature. The crystals formedare filtered and recrystallized from chloroform. Thus 200 mg of puretitle compound are obtained corresponding to 90% yield.

C₁₄ H₈ NO₂ requires: C 75.33 H 4.06 N 6.28 found: C 75.20 H 3.95 N 6.15MS m/z: 223 IR cm⁻¹ (KBr): 3300-2500 (COOH, OH), 2200 (CN), 1690 (COOH),1600-1560-1510 (C═C)

Following the above reported procedure and starting from the appropriatealdehyde derivative the following compounds can be prepared:

2-cyano-3-(2-hydroxynaphth-1-yl)acrylic acid;

2-cyano-3-(3-hydroxynaphth-1-yl)acrylic acid;

2-cyano-3-(4-hydroxynaphth-1-yl)acrylic acid;

2-cyano-3-(3-hydroxynaphth-2-yl)acrylic acid;

2-cyano-3-(4-hydroxynaphth-2-yl)acrylic acid;

2-cyano-3-(2-hydroxy-5,6,7,8-tetrahydronaphth-1-yl)acrylic acid;

2-cyano-3-(3-hydroxy-5,6,7,8-tetrahydronaphth-1-yl)acrylic acid;

2-cyano-3-(4-hydroxy-5,6,7,8-tetrahydronaphth-1-yl)acrylic acid;

2-cyano-3-(1-hydroxy-5,6,7,8-tetrahydronaphth-2-yl)acrylic acid;

2-cyano-3-(3-hydroxy-5,6,7,8-tetrahydronaphth-2-yl)acrylic acid;

2-cyano-3-(4-hydroxy-5,6,7,8-tetrahydronaphth-2-yl)acrylic acid;

2-cyano-3-(3-hydroxyquinolin-2-yl)acrylic acid;

2-cyano-3-(4-hydroxyquinolin-2-yl)acrylic acid;

2-cyano-3-(2-hydroxyquinolin-3-yl)acrylic acid;

2-cyano-3-(4-hydroxyquinolin-3-yl)acrylic acid;

2-cyano-3-(2-hydroxyquinolin-4-yl)acrylic acid; and

2-cyano-3-(3-hydroxyquinolin-4-yl)acrylic acid.

EXAMPLE 4

3-(1-hydroxy-5,6,7,8-tetrahydronaphth-2-yl)acrylic acid I, Y=B, R=i, R₁=R₂ =H, R₃ =OH, n=1

A mixture of 1-hydroxy-5,6,7,8-tetrahydro-2-naphthaldehyde (176 mg, 1mmol), malonic acid (208 mg, 2 mmol), piperidine (85 mg, 1 mmol) andpyridine (1 ml) are heated at 100° C. for 3 h and at reflux for 1/2 h.

The mixture is then cooled and poured onto ice and hydrochloric acid.The precipitated material is separated by filtration and thenrecrystallized from ethanol thus giving pure title compound in 80% yield(174 mg).

C₁₃ H₁₄ O₃ calc.: C 71.54 H 6.46 found: C 71.35 H 6.30 MS m/z: 218 IRcm⁻¹ (KBr): 3300-2500 (COOH, OH), 1690 (COOH), 1640 (C═C)

EXAMPLE 5

2-(4-hydroxyphenyl)-3-(naphth-2-yl)acrylic acid I, Y=A, R=i, R₂ =H, R₃=OH, n=zero

A mixture of 2-naphthaldehyde(156 mg, 1 mmol), 4-hydroxyphenylaceticacid (152 mg, 1 mmol), triethylamine (101 mg, 1 mmol) and aceticanhydride (510 mg, 5 mmol) are heated for 5 h at 100° C.

After cooling, the mixture is treated with diluted hydrochloric acid andthen extracted with ethylacetate. The organic layer is separated andreextracted with diluted sodium hydroxide solution. The aqueous phase isseparated and the raw product isolated by precipitation withhydrochloric acid. Pure title compound is obtained by crystallizationfrom isopropanol in 60% yield (174 mg).

C₁₉ H₁₄ O₃ calc.: C 78.60 H 4.86 found: C 78.69 H 4.89 MS m/z: 290 IRcm⁻¹ (KBr): 3600-2500 (OH, COOH), 1680 (COOH), 1600, 1585, 1510 (C═C)

By proceeding analogously the following compounds can be prepared:

2-(4-hydroxyphenyl)-3-(quinolin-3-yl)acrylic acid

C₁₈ H₁₃ NO₃ calc.: C 74.21 H 4.50 N 4.81 found: C 73.85 H 4.37 N 1.53 MSm/z: 291 IR cm⁻¹ : 3380 (OH), 3100-1800 (COOH), 1670 (COOH) 1605, 1580,1510 (C═C)

2-(4-hydroxyphenyl)-3-(naphth-1-yl)acrylic acid;

2-(4-hydroxyphenyl)-3-(5,6,7,8-tetrahydronaphth-1-yl)acrylic acid;

2-(4-hydroxyphenyl)-3-(5,6,7,8-tetrahydronaphth-2-yl)acrylic acid;

2-(4-hydroxyphenyl)-3-(quinolin-2-yl)acrylic acid; and

2-(4-hydroxyphenyl)-3-(quinolin-4-yl)acrylic acid.

EXAMPLE 6

2-(4-hydroxyphenyl)-3-(naphth-2-yl)acrylamide I, Y=A, R=i, R₂ =H₁ R₃=NH₂, n=zero

A mixture of 2-naphthaldehyde (156 mg, 1 mmol), 4-hydroxyphenylaceticacid (152 mg, 1 mmol), triethylamine (101 mg, 1 mmol) and aceticanhydride (510 mg, 5 mmol) are heated for 5 h at 100° C. The mixture istreated with diluted hydrochloric acid after cooling and then extractedwith ethylacetate. The organic layer is extracted with sodium hydroxidesolution. After separation of the aqueous phase the raw carboxilic acidis isolated by precipitation with hydrochloric acid.

The raw carboxylic acid is transformed in its acid chloride by treatmentwith thionyl chloride (1190 mg, 10 mmol) in boiling benzene (5 ml) for 2h. After evaporation to dryness under vacuum the raw acid chloride istransformed to the amide by reaction with diluted ammonium hydroxide atroom temperature for 1 h. The raw product is obtained by filtration,washing and drying under vacuum. Crystallization from isopropanolfurnishes pure title compound in 50% yield (145 mg).

C₁₉ H₁₅ NO₂ calc.: 78.87 H 5.23 N 4.84 found: C 78.71 H 5.09 N 4.65 MSm/z: 289 IR cm⁻¹ (KBr): 3600-3100 (OH, NH), 1650 (CONH) 1610, 1560, 1510(C═C)

According to the above described procedure the following compounds canbe prepared:

2-(4-hydroxyphenyl)-3-(quinolin-3-yl)acrylamide

C₁₈ H₁₄ N₂ O₂ calc C 74.47 H 4.86 N 9.65 found C 74.32 H 4.71 N.9.51 MSm/z: 290 IR cm⁻¹ (KBr): 3450, 3320 (NH), 3500-2300 (OH), 1665(CONH),1615, 1565, 1510, 1490 (C═C,C═N)

2-(4-hydroxyphenyl)-3-(naphth-1-yl)acrylamide;

2-(4-hydroxyphenyl)-3-(5,6,7,8-tetrahydronaphth-1-yl)acrylamide;

2-(4-hydroxyphenyl)-3-(5,6,7,8-tetrahydronaphth-2-yl)acrylamide;

2-(4-hydroxyphenyl)-3-(quinolin-2-yl)acrylamide; and

2-(4-hydroxyphenyl)-3-(quinolin-4-yl)acrylamide.

EXAMPLE 7

2-(4-hydroxyphenyl)-3-(naphth-2-yl)acrylonitrile I, Y=A, R=j, R₂ =H,n=zero

To a solution of 2-naphthaldehyde (156 mg, 1 mmol) and4-hydroxybenzylcyanide (133 mg, 1 mmol) in dry ethanol (2ml) is addedportionwise under cooling sodium ethoxide (204 mg, 3 mmol) and theresulting solution is maintained for 96 h at room temperature. Then thesolution is poured onto a mixture of ice and diluted hydrochloric acid.The precipitate formed is filtered off, washed with ice-cooled aqueousethanol and dried in a vacuum-oven.

Thus, pure title compound is obtained in 80% yield (217 mg).

C₁₉ H₁₃ NO calc. C 84.11 H 4.83 N 5.16 found C 83.91 H 4.87 N 4.86 MSm/z: 271 IR cm⁻¹ (KBr): 3340 (OH), 2220 (CN), 1605, 1585, 1510 (C═C).

EXAMPLE 8

2-cyano-3-(1-hydroxy-5,6,7,8-tetrahydronaphth-2-yl)acrylamide I, Y=B,R=a, R₁ =R₂ =H, R₃ =NH₂, n=1

The starting material for this de-etherification example is2-cyano-3-(1-methoxy-5,6,7,8-tetrahydronaphth-2-yl) acrylamide, whichcan be obtained according to the procedure described in Example 1.

To a stirred solution of2-cyano-3-(1-methoxy-5,6,7,8-tetrahydronaphth-2-yl)acrylamide (256 mg, 1mmol) in anhydrous dichloromethane (10 ml) is added at -78° C. undernitrogen, over a period of 10 min, a 1.0M solution of boron tribromidein dichloromethane (3 ml, 3 mmol). The resulting mixture is stirred foranother 1 h at -78° C. and then allowed to warm to room temperature.After stirring for 1.5 h at 20°-25° C. the mixture is cooled to -10° C.and then quenched by the dropwise addition of water (10 ml) over a10-min period. After addition of ethylacetate (10 ml) the organic layeris separated, washed with water, dried with Na₂ SO₄ and evaporated undervacuum to dryness. The residue is crystallized from ethanol thus giving169 mg of pure title compound (yield 70%).

C₁₄ H₁₄ N₂ O₂ calc. C 69.40 H 5.82 N 11.56 found C 69.30 H 5.85 N 11.41MS m/z: 242 IR cm⁻¹ (KBr): 3500-3100 (NH,OH), 2210 (CN), 1685 (CONH₂),1610, 1590, 1560

According to the above described procedure and starting from thecorresponding phenolic methylether, the compounds mentioned in Examples1,2 and 3 can be obtained.

EXAMPLE 9

2-cyano-3-(1-acetoxy-5,6,7,8-tetrahydronaphth-2-yl)acrylamide I-Y=B,R=a, R₁ =COCH₃, R₂ =H, R₃ =NH₂, n=1

The starting material for this acylation example is2-cyano-3-(1-hydroxy-5,6,7,8-tetrahydronaphth-2-yl) acrylamide, whichmay be obtained according to the procedure described in example 1.

To a cooled solution of2-cyano-3-(1-hydroxy-5,6,7,8-tetrahydronaphth-2-yl)acrylamide(242 mg, 1mmol in dry pyridine (0.5 ml) is added acetic anhydride (204 mg, 2 mmol)and the mixture maintained at 0°-5° overnight. Thereupon the mixture isconcentrated under vacuum, the residue dissolved in dichloromethane, theorganic layer washed with water and then evaporated under reducedpressure. The crude product is crystallized from chloroform/methanol toyield pure title compound in 90% yield (256 mg).

C₁₆ H₁₆ N₂ O₃ calc: C 67.59 H 5.67 N 9.85 found: C 67.41 H 5.45 N 9.71MS m/z: 284 IR cm⁻¹ (KBr): 3300÷3200 (NH), 2200 (CN), 1750 (CH₃ COO),1690 (CONH₂), 1610, 1590, 1560

According to the above described procedure the phenols obtained inExamples 1 to 9 can be transformed into the corresponding C₂ -C₆alkanoyl derivatives.

EXAMPLE 10

Tablets each weighing 0.150 g and containing 25 mg of the activesubstance, can be manufactured as follows: composition (for 10000tablets):

    ______________________________________                                        2-cyano-3-(1-hydroxynaphth-2-yl)acrylamide                                                              250    g                                            Lactose                   800    g                                            Corn starch               415    g                                            Talc powder               30     g                                            Magnesium stearate        5      g                                            ______________________________________                                    

The 2-cyano-3-(1-hydroxynaphth-2-yl)acrylamide, the lactose and half thecorn starch are mixed; the mixture is then forced through a sieve of 0.5mm mesh size. Corn starch (10 g) is suspended in warm water (90 ml) andthe resulting paste is used to granulate the powder. The granulate isdried, comminuted on a sieve of 1.4 mm mesh size, then the remainingquantity of starch, talc and magnesium stearate are added, carefullymixed and processed into tablets.

EXAMPLE 11

Capsules, each dosed at 0.200 g and containing 20 mg of the activesubstance can be prepared. Composition for 500 capsules:

    ______________________________________                                        2-cyano-3-(3-hydroxynaphth-2-yl)acrylamide                                                              10     g                                            Lactose                   80     g                                            Corn starch               5      g                                            Magnesium stearate        5      g                                            ______________________________________                                    

This formulation is encapsulated in two-piece hard gelatin capsules anddosed at 0.200 g for each capsule.

We claim:
 1. A compound of formula (I') ##STR11## wherein Y is abicyclic ring system chosen from (A) and (B), ##STR12## R₁ is hydrogen,C₁ -C₆ alkyl or C₂ -C₆ alkanoyl; R₂ is hydrogen, halogen, cyano or C₁-C₆ alkyl;n is from 1 to 3 when Y is a ring system A; and n is 0, 1 or 2when Y is a ring system B; or a pharmaceutically acceptable saltthereof; and wherein each of the substituents OR₁, R₂ and ##STR13## maybe independently on either of the aryl moieties of the bicyclic ringsystem (A) whereas only the benzene moiety may be substituted in thebicyclic ring system (B).
 2. A compound of formula (I'), according toclaim 1, wherein Y and n are as defined in claim 1;R₁ is hydrogen, C₁-C₄ alkyl or C₂ -C₄ alkanoyl and R₂ is hydrogen;or a pharmaceuticallyacceptable salt thereof.
 3. A compound of formula (I'), according toclaim 1, wherein Y is as defined in claim 1;R₁ and R₂ are hydrogen; n iszero or 1; or a pharmaceutically acceptable salt thereof.
 4. A compoundselected from the group consisting of the following, which may be eitherZ- or E- diastereoisomers or Z,E- mixtures of saiddiastereoisomers:3-[(3-hydroxy-1-naphthyl)methylene]-2-oxindole;3-[(4-hydroxy-1-naphthyl)methylene]-2-oxindole;3-[(1-hydroxy-2-naphthyl)methylene]-2-oxindole;3-[(4-hydroxy-2-naphthyl)methylene]-2-oxindole;3-[(3-hydroxy-5,6,7,8-tetrahydronaphth-1-yl)methylene]-2-oxindole;3-[(4-hydroxy-5,6,7,8-tetrahydronaphth-1-yl)methylene]-2-oxindole;3-[(1-hydroxy-5,6,7,8-tetrahydronaphth-2-yl)methylene]-2-oxindole;3[(4-hydroxy-5,6,7,8-tetrahydronaphth-2-yl)methylene]-2-oxindole;and, ifthe case, the pharmaceutically acceptable salts thereof.
 5. A compoundaccording to claim 1 which is3-[(1,4-dihydroxy-5,6,7,8-tetrahydronaphth-2-yl)methylene]-2-oxindole.6. A pharmaceutical composition containing at least one of a suitablecarrier and diluent and, as an active principle, a therapeuticallyeffective amount of a compound of formula (I') as defined in claim 1 ora pharmaceutically acceptable salt thereof.
 7. A method of treating ahuman or animal patient in need of treatment with a tyrosine kinaseinhibitor, which method comprises administering thereto atherapeutically effective amount of a compound of formula (I') asdefined in claim 1 or a pharmaceutically acceptable salt thereof.